Late-onset late life major depression (late-onset LLMD) is a heterogeneous disorder with respect to etiology and outcome. Both longitudinal and post-mortem studies have found that a subset of elderly individuals with late-onset LLMD who are cognitively intact at the time of their first depressive episode will develop progressive cognitive decline and/or a clinical and histopathologic diagnosis of Alzheimer's disease (AD) within relatively brief follow-up periods. The many decades required for the pathologic AD criteria to develop implies that the depressive episode may represent a preclinical or prodromal phase of AD in a subset of individuals. However, there are presently no biological markers to identify those individuals with late-onset LLMD who have prodromal AD. Results from studies in healthy elderly conducted by our group and others suggest that higher baseline plasma amyloid beta peptide-Ma (A/?42) level, higher A[unreadable]42/A/?40 ratios and greater reductions in A[unreadable]42 during longitudinal follow-up, are associated with greater cognitive decline and/or incident AD. There is also evidence from our cross-sectional pilot study of elevated plasma A/?42 and A$42/A[unreadable]40 ratio in elderly individuals with LLMD, and elevated CSF A/?42 levels have also been reported previously in individuals with major depression. Based on these earlier suggestive findings, the major objectives of this proposal are: (1) to conduct a 3-year longitudinal study to test the hypothesis that elderly individuals with late-onset LLMD will have higher plasma A/942 level and A#42/A[unreadable]40 ratio and greater reductions in A[unreadable]42 during longitudinal follow-up relative to controls, and (2) to examine whether measures of A/042 will be associated with greater cognitive decline and/or the development of AD in elderly individuals with late-onset LLMD. Another goal is to determine if changes in plasma A/ff42 levels are paralleled by similar changes in cerebrospinal fluid (CSF) A/?42 in a subset of subjects. If these hypotheses are confirmed, then the determination of plasma A/?42 might become an easily obtainable marker to identify those individuals with late-onset LLMD who may have prodromal AD.